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International Clinical Trials

A Better Deal in Europe

Bringing a unified approach to the interpretation of the Clinical Trial Directive has proved far from straightforward; Peggy Cance and Karen Goode at EUDRAC investigate the impact of the voluntary harmonisation procedure as it seeks to facilitate a more uniform reading of clinical trial applications

Before the implementation of the Clinical Trial Directive (CTD) 2001/20/CE in 2004, the conduct of clinical trials in Europe varied from one country to another; there were different national approaches to many of the procedures involved such as the approval and notification systems, documentation requirements and timelines. The aim of the CTD was to harmonise the way clinical trials were performed in Europe. It was implemented across member states by the Clinical Trial Facilitation Group (CTFG), set up in 2004 by the Heads of Medicines Agencies (HMA) to co-ordinate this task.

Now, seven years after it was introduced, there is no doubt that the CTD has enhanced the performance of clinical trials in Europe, but there is still room for improvement. There have been differences in countries’ interpretation of the CTD, so there is still a lack of harmonisation in some areas, particularly the documentation package and the assessment procedure. Ultimately, this has led to a number of divergent decisions by the competent authorities (CA) on the same multinational clinical trial application (CTA), causing costly delays in the overall clinical trial procedure.

To address these issues, in 2009 the CTFG introduced a voluntary harmonisation procedure (VHP). Essentially the VHP sets out a coordinated assessment procedure between the member state with fixed review timelines.

DEVELOPMENT OF THE VHP

A pilot study of the VHP, as first proposed by the CTFG, was conducted between April and August 2009. Applications were invited for:

  • Multinational clinical trials involving more than three member states
  • Investigational medicinal products without a marketing authorisation in any EU member state
  • Special clinical trials (for example large Phase 3, first-in-human, or orphan drug)

This pilot study included a ‘pre-procedural step’, whereby a letter of intention to participate had to be submitted before the fifth day of the month, justifying the eligibility of the clinical trial for the VHP. Following this, the VHP was revised and an updated version was launched in March 2010. Essentially, the scope of the VHP was enlarged and the timelines shortened. The main changes were as follows:

  • All clinical trials would be accepted in the VHP if at least three member states were involved
  • The ‘pre-procedural step’ was removed to shorten timelines
  • Substantial amendments to clinical trial applications were included

By December 2010, the CTFG had received 47 applications to participate in the VHP.

VHP WORK FLOW

Currently, the VHP consists of three phases (see Table 1).

Phase 1: Request for VHP Phase and Validation

Sponsors submit a ‘request for VHP’, including a Core CTA dossier to VHP‑CFTG@VHP-CTFG.eu, and a VHP coordinator is then appointed. This application request includes the documents listed in Table 2.

An acknowledgement of receipt is sent to the sponsor by the VHP coordinator including the assignment of a VHP number. The VHP coordinator then forwards the dossier to the member state concerned. Within five working days, the applicant is informed whether its VHP request is valid and if all the member states agree to participate. Any missing information should be submitted within three days.

Phase 2: Assessment Phase of the Core Clinical Trial Application (CTA) Dossier by the National CA

The participating member states have a maximum of 20 calendar days to complete their assessment and inform the VHP coordinator of any grounds for non-acceptance (GNA). Since July 2009, the VHP has included the concept of a ‘leading member state’ to lead the consolidation of questions issued by the other member states. From these questions, the leading member state must facilitate the production of a list of ‘essential’ issues to be addressed by the sponsor before the authorisation can be granted.

The VHP-coordinator forwards the applicant responses to the participating member state, who have seven days to assess the responses and reach a consensus on the acceptability of the application. Table 3 provides the average processing times for Phase 2 of the VHP.

Phase 3: National Phase – Submission of National CTA to Each of the CA Involved

Once the assessment phase has been completed, the sponsor should submit a formal CTA application to each participating member state. This should be done within 20 calendar days of receipt of the VHP approval.

In practice, sponsors have submitted their national applications within 30 calendar days of receipt of the VHP approval, and this has been accepted by the member state. Due to specific national issues (for example, an ethics committee (EC) opinion required prior to CA approval), the mean time for national approval is 19 days.

If a sponsor decides to submit a CTA application to an additional member state not previously involved in the VHP procedure, the member state may decide to adopt the VHP decision and grant an expedited review. However, this is the decision of the individual member state involved.

STRENGTHS & WEAKNESSES OF THE VHP

It is clear that there are advantages and disadvantages when implementing the procedure. When thinking about the strengths, bear in mind the:

  • Fixed timelines for the validation and assessment of the CTA by all concerned member states
  • Faster submission of core CTA, as national documents (site lists for example) are only required at Phase 3 of the VHP
  • Applicant receives a single consolidated list of questions, which has been discussed by all concerned member states
  • Total number of points issued to applicant as GNA is greatly reduced, especially with the introduction of the leading member state
  • Reduction in applicants’ workloads and use of internal resources

It has to be recognised that the VHP has introduced a stronger degree of co-operation between member states, and therefore the harmonisation of the review procedure for CTAs for multinational clinical trials.

Some of the fi rst companies that took part in the VHP have shared their experiences; overall they considered the VHP to be a positive one, with good collaboration with the CTFG resulting in more timely approvals of CTAs by the CA involved.

In terms of the weaknesses, the following points need to be understood:

  • EC review is outside the scope of the VHP, therefore in some member states the CA will not be able to issue an approval if there is a rejection from the EC (this could lead to an administrative rejection by the CA). In other cases EC approval is required before the CA can issue the national regulatory approval, possibly delaying the commencement of the clinical trial
  • A full IMPD has to be submitted if any of the countries involved in the VHP has not previously authorised a clinical trial with the IMP concerned (even if the majority of member states involved would have accepted a simplifi ed IMPD)
  • It does not allow for the fact that different CAs can have vastly different workloads; increasing VHP demands could lead to the introduction of submission slots (as for marketing authorisation applications through the decentralised procedure (DCP) route); in an earlier response to the concept paper on the VHP, the ABPI deemed that this would be unacceptable for clinical trials “…where About the authors development times impact even more on patient access to new safe and effective compounds”

The VHP has not been able to address all of the fundamental problems linked to a divergent interpretation of the EU CTD. In particular, the VHP does not solve the current problems relating to harmonisation of procedures and decisions between national CA and EC.

CONCLUSION

The VHP has addressed some of the key issues with the CTD and highlighted some that remain. The VHP has provided a process through which some of the criticisms of the CTD have been addressed without the need for new legislation to be introduced. It has been generally successful in facilitating a harmonised regulatory assessment of CTAs across member states. However, it has not addressed many other issues linked to the interpretation of the CTD, notably those where CTA approval is linked to EC review.

According to the EudraCT database for example, the number of trials across EU declined by 10 per cent between 2007 and 2009 and patient participation decreased by 30 per cent. These fi gures show that there is a still a need to improve the regulatory environment in order to make the EU a more attractive place to conduct clinical trials. The CTFG believes that the VHP is the most cost-effective procedure for the conduct of multinational trials and, as such, should be supported by the European Commission with the provision of funding for staff and infrastructure.

The VHP remains a priority for CA and the CTFG has committed to expand and improve the process, including further development of the concept of the leading member state. To address this, in 2012, the European Commission has plans to put forward a legislative proposal to revise the CTD. A public consultation on the proposed changes was held in October 2009 and a concept paper was submitted for public consultation in February 2011. So far, over 180 responses have been received to this latest concept paper. These hail from a variety of sources ranging from concerned individuals to representatives of industry and academia, medical associations and patient treatment groups.

The topics for consultation incorporate the principles of the VHP, such as the co-ordinated assessment procedure (CAP) and a harmonised approach to clinical trial procedures. The concept paper endorses a risk-based approach to assessment, whereby very low risk clinical trials, as justifi ed by the sponsor would undergo an expedited review, akin to a ‘notification procedure’, as currently exists for Type 1A variations.

The MHRA has published their response to the concept paper. It has been largely positive, particularly regarding the CAP, although it foresees that the proposal to submit all documentation via a single EU portal for both regulatory and ethical approval may be challenging. It also maintains that separate submissions should remain an option, highlighting that ethics committee review is also concerned with the design and relevance of the study to the local population. The CTD affects 30 member states. The initiative of the CTFG to promote the VHP and the subsequent proposal by the EC to amend the CTD, both aim to harmonise the differences in clinical trial procedures in all of these countries. To date, there have been, on average, six responses to the concept paper per country.

The proposal, due in 2012, will be welcomed throughout Europe as it is expected that the conduct of clinical trials will become more uniform as a result. This should enable new medicines to be brought to patients more quickly and more cheaply.

References

  1. Assessment of the functioning of the ‘Clinical Trials Directive’ 2001/20/EC, Public Consultation Paper, ENTR/F/2/SF D(2009) 32674, 09/10/2009
  2. Guidance document for a Voluntary Harmonisation Procedure (VHP) for the assessment of multinational Clinical Trial Applications, version sponsor 1.1, Pilot Phase proposed by CFTG
  3. Guidance document for a Voluntary Harmonisation Procedure (VHP) for the assessment of multinational Clinical Trial Applications, CTFG// VHP/2010/Rev1, March 2010
  4. Brizmohun N, Ringing in the changes for regulatory affairs in 2010, Regulatory Affairs Journal 21(1): pp39-40, 2010
  5. Kenny M, Worldwide update, Regulatory Affairs Journal 21(2): pp134-136, 2010
  6. Hartmann M and Hartmann-Vareilles F, How to avoid further legislative fragmentation of clinical research in the European Union, Regulatory Affairs Journal 21(3): pp161-166, 2010
  7. Gaymond N and Abouzeid C, Optimism in the UK biosciences sector, Regulatory Affairs Journal 22(1): pp18-19, 2011
  8. Bonsu A, Colley A, Karine E, Walker C and Yates A, Initial experiences with the VHP – a perspective from industry, Regulatory Rapporteur 8(3): pp8-11, 2011
  9. Revision of the ‘Clinical trials directive’ 2001/20/EC, concept paper submitted for public consultation, SANCO/C/8/PB/SF D(2011) 143488, 09/02/2011
  10. Revision of the Clinical Trials Directive 2001/20/EC. UK response to Concept Paper, 17 June 2011

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Peggy Cance is a Regulatory Affairs Consultant at EUDRAC France, a regulatory affairs consulting company. Peggy has six years’ regulatory experience working on clinical trial submissions and product lifecycle management. Before embarking on her regulatory career, she worked in clinical trial data management. Peggy holds a DEA (Masters) in Pharmacology and Biology (cellular and molecular) from the University of Nice, France. Email: peggy.cance@eudrac.com

Karen Goode is a Senior Regulatory Affairs Consultant at EUDRAC Ltd, based in the UK. Karen has 10 years’ regulatory experience working on new MAAs, product lifecycle management and medical devices. Before embarking on her regulatory career, Karen worked as a Senior Clinical Research Associate. Karen gained a BSc in pharmacology from University College, London, and a Post-Graduate Diploma in Clinical Science from the University of Wales. Email: karen.goode@eudrac.com

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